The phosphatidylinositol-3-kinases superfamily comprises 4 different PI3K related lipid or protein kinases. Class I, II and III are lipid kinases that differ from their substrate specificities whereas class IV PI3K also called Pβ-kinase-related protein kinase (PIKK) are protein kinases. Class I PI3Ks comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001)). Aberrant regulation of PI3K, which often increases survival and proliferation through activation of AKT kinase is one of the most prevalent events in human cancer and has been shown to occur at multiple levels (Liu et al., Nat Rev Drug Discov 8:627-644 (2009)). For instance, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Huang et al., Science 318: 1744-1748 (2007), Zhao & Vogt, Oncogene 27:5486-5496 (2008)). The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3′ position of the inositol ring and in so doing antagonizes PI3K activity, is functionally mutated or deleted in a variety of tumors (Keniry & Parsons, Oncogene 27:5477-5485 (2008)). Some studies indicate that the failure to express PTEN can mediate a shift of signaling dependence from the PI3Kα to the β-isoform (Wee et al, Porc Natl Acad Sci USA 105:13057-13062 (2008)). Therefore, inhibition of both class I PI3K α and β-isoforms can be particularly advantageous in cancers that are deficient in PTEN phosphatase.
Published international patent application WO2007/084786 describes substituted pyrimidine molecules that inhibit PI3K.
It is well established that activation of Akt results in the stimulation of the kinase activity of the mammalian target of rapamycin (mTOR). mTOR is a protein kinase and a member of the class IV PI3K. In mammalian cells, mTOR is found in two distinct protein complexes called mTORC1 and mTORC2. Activation of mTORC1 is dependent on active PI3K and Akt kinases. Regulation of mTORC2 activation is more complex. mTORC2 is responsible for enhancement of Akt kinase activity via phosphorylation of serine residue 473 (Sarbassov et al., Science 307:1098-1101 (2005), Bayascas & Alessi, Mol Cell 18(2):143-145 (2005)). Catalytic inhibition of class I PI3K isoforms concomitant with inhibition of mTOR might therefore represent an additional benefit, potentially introducing a stronger effect on the PI3K-Akt pathway.
Cutaneous squamous cell carcinoma (SCC) represents the second most frequent human skin cancer, commonly preceded by actinic keratosis (AK). The pathogenesis of AK and cutaneous SCC has been associated with chronic UV exposure as one major risk factor (Salasche, J Am Acad Dermatol 42: 4-7 (2000)). An enhanced activity of PI3K/Akt/mTOR pathway has been suggested in a previous study (Chen et al., Br J Dermatol; 160 (2):442-445 (2009)). It has been shown that prolonged UV-B irradiation causes a downregulation of PTEN expression at the mRNA and protein level in human keratinocytes in vitro, promoting their survival and growth (Ming et al., Oncogene; 29(4):492-502 (2010)). Based on recent literature, there is a causal link between chronic UV-irradiation and downregulation of PTEN (Darido et al., Cancer Cell; 20(5):635-648 (2011)). Therefore, cutaneous SCC and AK and chronically sun-damaged skin can all be associated with a deficiency of PTEN expression leading to an activation of the PI3K/Akt/mTOR signaling pathway.